TIR-domain containing cell surface receptors such as the Toll-like receptors and the IL-1 and IL-18 receptors play critical roles in innate immunity and have been implicated in the pathogenesis of autoimmunity. TLRs, for example, recognize pathogenic or endogenous ligands and provide a requisite signal for dendritic cell maturation and antigen presentation to T cells (13). Similarly, the proteins that mediate signaling from these receptors have also been shown to play important roles in the pathogenesis of autoimmune disorders. For example mice deficient in MyD88, an adaptor protein that directly interacts with the TIR domain are more susceptible to bacterial, fungal and parasitic infections. In addition, MyD88 deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) and streptococcal cell wall-induced arthritis (7, 11, 18).
The Interleukin-1 Receptor Associated Kinase (IRAK) family is comprised of four family members IRAK-1, IRAK-2, IRAK-3/M, and IRAK-4. These proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain. Whereas IRAK-1 and IRAK-4 have kinase activity, IRAK-2 and IRAK-3/M are catalytically inactive. Upon activation of their upstream cognate receptors, IRAK-4 is thought to phosphorylate IRAK-1 resulting in the activation and autophosphorylation of IRAK-1 and subsequent phosphorylation of downstream substrates. The hyperphosphorylation of IRAK-1 directs its dissociation from the receptor complex and its eventual ubiquitylation and proteasomal degradation. Phosphorylation of downstream substrates such as Pellino-2 ultimately leads to the activation of the MAPKs such as p38 and c-Jun N-terminal kinase (JNK) and NF-kB followed by production of pro-inflammatory cytokines, chemokines, and destructive enzymes (8, 10, 22).
The role of IRAK-1 and IRAK-4 in innate immunity and in the pathogenesis of autoimmune diseases is emerging. Patients with destabilizing or null mutations in IRAK-4 demonstrate defects in TLR signaling and the production of pro-inflammatory cytokines such as IL-1 and TNF (2, 3, 5, 17), as well as antiviral cytokines such as IFNα and IFNβ (27). These patients demonstrate an increased susceptibility to gram-positive bacterial infections although they are generally resistant to gram-negative bacterial, viral, and fungal infections. Similarly, IRAK-4 deficient mice have defects in TLR- and IL-1-mediated cytokine production and increased susceptibility to infection. IRAK-1 deficient mice demonstrated a loss of responsiveness to lipopolysaccharides (LPS), IL-1, IL-18 as well as impaired Th1 development (9). These mice were resistant to experimental autoimmune encephalomyelitis, exhibiting little or no CNS inflammation.
Accordingly, compounds that modulate the function of IRAK-1 and/or IRAK-4 represent an attractive approach to the development of therapeutic agents for the treatment of inflammatory, cell proliferative and immune-related conditions and diseases associated with IRAK-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic disease, psoriasis, asthma, graft rejection, cancer and sepsis.
Activation of SYK tyrosine kinase is an important in the signally pathways following the activation of mast cells (J. A. Taylor et al., Molec. and Cell Biol., 1995, 15, 4149). SYK kinase activation and activity is considered for Fc epsilon RI (high-affinity IgE receptor)-mediated release of mediators from mast cells. Inhibitors of SYK kinase can thus block the release of allergic and pro-inflammatory mediators and cytokines, and are potentially useful for treatment of inflammatory and allergic disorders such as asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, conjunctivitis, psoriasis, scleroderma, urticaria, dermatitis and allergic rhinitis.